Method of treating depression

ABSTRACT

Methods are disclosed herein for treating depression in the subject. A method includes the use of Botulinum toxin to cause paralysis of a facial muscle, such as the depressor anguli oris, procerus, frontalis, orbicularis oculi, or corrugator supercilii muscle to treat depression in the subject.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of U.S. application Ser. No. 15/388,840, filed onDec. 22, 2016, now U.S. Pat. No. 9,950,045, which is a continuation ofU.S. application Ser. No. 14/746,299, filed Jun. 22, 2015, now U.S. Pat.No. 9,533,029, which is a continuation of U.S. application Ser. No.13/789,216, filed Mar. 7, 2013, U.S. Pat. No. 9,060,964, which is acontinuation of U.S. application Ser. No. 12/813,373, filed on Jun. 10,2010, now U.S. Pat. No. 8,414,902, which is a continuation of U.S.patent application Ser. No. 10/773,785, filed on Feb. 6, 2004, now U.S.Pat. No. 7,758,872, which in turn claims the benefit of U.S. ProvisionalApplication No. 60/445,868, filed Feb. 7, 2003. All of the priorapplications are incorporated by reference herein in their entirety.

FIELD

This application relates to the field of psychiatry. In particular, thisapplication pertains to the discovery that agents that affect themovement of the facial muscles, such as botulism toxin, can be used inmethods of ameliorating depression.

BACKGROUND

The mood and anxiety disorders in their various permutations constitutea major source of personal suffering and impaired ability to engage inproductive work and interpersonal relationships. Between 5 and 9% ofwomen and between 2 and 3% of men meet the diagnostic criteria for majordepression at any time; 10-25% of all women suffer major depressionsometime in their lives, while 5-10% of men will develop majordepressive disorder (American Psychiatric Association, 1994).

Affective disorders, while characterized by depressed mood of varyingdegrees, exist in various forms. The various forms of depression aredefined and are separately diagnosed according to criteria given inhandbooks for psychiatry, for example in the Diagnostic and StatisticalManual of Mental Disorders 4th edition (DSM-IV) published by theAmerican Psychiatric Association, Washington, D.C. (1994). In theDSM-IV, depressive disorders are classified under mood disorders and aredivided into three types: major depressive disorder, dysthymic disorderand depressive disorder not otherwise specified (or “atypical”). Ingeneral, regardless of whether or not the depressive syndrome ismelancholic, atypical, or some admixture of the two, a diagnosis ofmajor depression is given when depressed mood is present, or loss ofinterest or pleasure in all activities is present, for at least twoweeks.

Thus, melancholic depression is characterized by continuously depressedmood and pervasive hopelessness, insomnia with early-morning awakening(with the inability to return to sleep), loss of appetite and weightloss, and excessive feelings of guilt. In contrast, so-called “atypical”depression is characterized by hypersomnia (oversleeping), hyperphagiaand weight gain, and—often—mood reactivity.

Major depressive disorder and dysthymic disorder are differentiatedbased on chronicity, severity and persistence. If less severe orincapacitating, depressed mood is considered dysthymia. Depressed moodcan occur in the form of a cycling mood abnormality such as bipolar mooddisorder, cyclothymia, or menstrual-related mood disorder. In dysthymicdisorder the depressed mood must be present most days over a period oftwo years.

Usually, major depressive disorder is characterized by its sharpcontrast to usual functioning. A person with a major depressive episodecan be functioning and feeling normal and suddenly develop severesymptoms of depression. By contrast, a person with dysthymic disorderhas chronic depression with less severe symptoms than major depression.Major depression is a major health problem and poses a tremendousfinancial burden on society due to lost self-support of individualssuffering from depression. Such individuals are often simply unable tofunction in everyday life situations, in part because of feelings ofextreme hopelessness and worthlessness. There is also a serious risk ofsuicide among such individuals. The diagnostic criteria for majordepression are well known to those skilled in the art, and comprise thecriteria set forth, for example, at DSM-IV 296.2 and 296.3.

Psychotic major depression has long been recognized as a distinctpsychiatric illness, having both psychotic and depressive components. Ina differential diagnosis, it is important that psychotic majordepression be distinguished from non-psychotic major depression, becauseeffective treatments and patterns of response to pharmacologic therapiesfor psychotic major depression are often different from those relatingto non-psychotic major depression. Successful treatment depends on theaccuracy of the initial diagnosis. (Glassman, Arch. Gen. Psychiatry38:424-427, 1981, Schatzberg, Am. J. Psychiatr. 149:733-745, 1992,Schatzberg, Annals N.Y. Acad. of Sci. 537:462, 1988). Psychotic majordepression is very common. It has been estimated that twenty fivepercent of depressed patients admitted to the hospital have psychoticmajor depression (Coryell Nerv. Ment. Dis. 172:521, 1984).

Mood and anxiety disorders very frequently coexist in the sameindividual. In this regard, it is now appreciated that almost allantidepressants improve anxiety symptoms. Conversely, the most popularanxiolytics, the benzodiazepines, improve mood acutely but are typicallyineffective or harmful to mood during chronic use.

The current psychopharmacologic treatments of affective and anxietydisorders have certain drawbacks. A significant portion of depressedpatients are resistant to treatment with existing antidepressants orcombinations thereof either because of non-responsiveness or because apositive effect wears off (breakthrough depression) or is inadequate(depression in partial remission). Troubling side effects, such asgastrointestinal disturbances or loss of libido, may also be seen withexisting antidepressants. Moreover, current psychopharmacologicanti-depressants have a latency of typically two weeks before the onsetof significant antidepressant activity. The most commonly usedanxiolytic medications, the benzodiazepines, have a number of majorlimitations: (a) tolerance to their effects rapidly develops, withincreasing doses becoming required to achieve the same effect; (b)benzodiazepine dependence is a standard occurrence after chronic use;(c) major withdrawal syndromes are seen—including grand malseizures—after abrupt discontinuation; (d) overdose is associated withrespiratory depression and sometimes death; (e) effects are potentiatedby alcohol, which is cross-tolerant with the benzodiazepines; and (0high abuse potential.

Depression is often associated with psychomotor abnormalities, such asincreased or retarded motor activity. Many depressed persons can also berecognized by their “depressed facies” in which the muscles of facialexpression assume a distressed or sad appearance. For example, the browmay be furrowed, the inner ends of the eyebrows raised, and the anglesof the mouth lowered such that the facial appearance is recognizably sadand/or anxious.

Although treatments for different types of depression do exist, there isa continuous search for new methods of treatment. Existing therapeuticapproaches still have disadvantages, such as the side effects of drugs,the long duration of treatments, and more importantly, the partialefficacy (or inefficacy) of existing treatments. Although some existingtreatments are effective, there is still a need for alternativetreatments, or therapeutic approaches that can be used in combinationwith existing treatment modalities.

SUMMARY OF THE INVENTION

A method is provided herein for treating depression. The method includesadministering to a person with an affective disorder a therapeuticallyeffective amount of drug that interferes with the ability of the facialmuscles to assume a depressed facies.

For example, a neurotoxin is administered to a facial muscle involved infrowning or scowling. The neurotoxin affects the ability of the subjectto frown and/or scowl, thereby treating depression. In one such method,a therapeutically effective amount of Botulinum toxin A can be injectedinto one or more of the frontalis, procerus, the corrugator supercilii,orbicularis oculi, or the depressor anguli oris (trianglaris muscle).Four major muscle groups are involved in frowning: the frontail,procerus, corrugator supercilii and orbicularis oculi (Weider et al.Derm Surg. 24:1172-1174, 1998. The corrugator supercilii is also knownas the “scowl” muscle. In a particular example, the Botulinum toxin A isinjected into the procerus muscle over the glabella.

The foregoing and other features and advantages will become moreapparent from the following detailed description of several embodiments,which proceeds with reference to the accompanying figures.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic diagram of a frontal view of the musculature ofthe human face and neck. Injection sites for a neurotoxin, including thefrontalis, procerus, the corrugator supercilii, orbicularis oculi, orthe depressor anguli oris muscles are shown.

FIG. 2 is a schematic diagram of a typical Botulinum toxin dose used totreat frown lines and the depressor anguli oris in a man. In thisspecific, non-limiting example, about 35 Units are injected into theprocerus, orbicularis oculi, and corrugator supercilii muscles. Numbersrefer to the number of BTX Units per injection site.

FIG. 3 is a schematic diagram of a typical Botulinum toxin dose used totreat frown lines in a woman. In this specific, non-limiting example,about 25 Units are injected into the procerus, orbicularis oculi, andcorrugator supercilii muscles. Numbers refer to the number of BTX Unitsper injection site.

FIG. 4 is a schematic diagram of a Botulinum toxin dose used to treatpatient 1. The numbers shown indicate the number of Units of Botulinumtoxin injected. In this example, about 40 Units are injected into theprocerus, orbicularis oculi, and corrugator supercilii muscles. Numbersrefer to the number of BTX Units per injection site.

FIG. 5 is a schematic diagram of a Botulinum toxin dose used to treatpatient 2. The numbers shown indicate the number of Units of Botulinumtoxin injected. In this example, about 30 Units are injected into theprocerus, orbicularis oculi, and corrugator supercilii muscles. Numbersrefer to the number of BTX Units per injection site.

FIG. 6 is a schematic diagram of a Botulinum toxin dose used to treatpatient 3. The numbers shown indicate the number of Units of Botulinumtoxin injected. In this example, about 30 Units are injected into theprocerus, orbicularis oculi, and corrugator supercilii muscles. Numbersrefer to the number of BTX Units per injection site.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS I. Abbreviations

BTX: Botulinum toxin

U: Units

II. Terms

Unless otherwise noted, technical terms are used according toconventional usage. Definitions of common terms in molecular biology maybe found in Benjamin Lewin, Genes V, published by Oxford UniversityPress, 1994 (ISBN 0-19-854287-9); Kendrew et al. (eds.), TheEncyclopedia of Molecular Biology, published by Blackwell Science Ltd.,1994 (ISBN 0-632-02182-9); and Robert A. Meyers (ed.), Molecular Biologyand Biotechnology: a Comprehensive Desk Reference, published by VCHPublishers, Inc., 1995 (ISBN 1-56081-569-8).

In order to facilitate review of the various embodiments of thisdisclosure, the following explanations of specific terms are provided:

Ameliorating or ameliorate: Any indicia of success in the treatment of apathology or condition, including any objective or subjective parametersuch as abatement, remission or diminishing of symptoms or animprovement in a patient's physical or mental well-being. Ameliorationof symptoms can be based on objective or subjective parameters;including the results of a physical examination and/or a psychiatricevaluation. For example, a clinical guide to monitor the effectiveamelioration of a psychiatric disorder, such as depression, is found inthe Structured Clinical Interview for DSM-IV Axis I mood disorders(“SCID-P”) (see fourth edition of Diagnostic and Statistical Manual ofMental Disorders (1994) Task Force on DSM-IV, American PsychiatricAssociation (“DSM-IV”); Kaplan, Ed. (1995); Comprehensive Textbook ofPsychiatry/VI, vol. 1, sixth ed., pp 621-627, Williams & Wilkins,Baltimore, Md.).

Anti-Depressant Medications: A pharmaceutical agent that is administeredas a treatment for depression. Anti-depressant medications includesynthesized chemical compounds as well as naturally occurring or herbalremedies such as St. John's Wort. Generally, these medications areadministered orally, but they may also be administered in any form ofuse to a medical practitioner. Examples of antidepressant medicationsinclude tricyclic antidepressants, which generally affect the twochemical neurotransmitters, norepinephrine and serotonin. Tricyclicantidepressants include imipramine, amitriptyline, nortriptyline, anddesipramine. Monoamine oxidase inhibitors (MAOIs) are also used asantidepressants. MAOIs approved for the treatment of depression includephenelzine (NARDIL®), tranylcypromine (PARNATE®), and isocarboxazid(MARPLAN®). Medications that primarily affect the neurotransmitterserotonin, termed selective serotonin reuptake inhibitors (SSRIs), arealso used as antidepressants. These include escitalopram HBr (LEXAPRO®),fluoxetine (PROZAC®), sertraline (ZOLOFT®), fluvoxamine (LUVOX®),paroxetine (PAXIL®), and citalopram (CELEXA®). Additional medication ofuse affect both norepinephrine and serotonin, for example venlafaxine(EFFEXOR®) and nefazadone (SERZONE®), or agents such as phenelzine(NARDIL®), tranylcypromine (PARNATE®), mirtazepine (REMERON®),nefazodone (SERZONE®), triazolopyridine (TRAZODONE®), and bupropion(WELLBUTRIN®).

Botulinum toxin: A toxin produced by the bacterium Clostridiumbotulinum, but which may either be obtained from a natural source ormade by synthetic means. Seven immunologically distinct Botulinumneurotoxins have been characterized, these being respectively Botulinumneurotoxin serotypes A, B, C₁, D, E, F and G, each of which isdistinguished by neutralization with type-specific antibodies. Thedifferent serotypes of Botulinum toxin vary in the animal species thatthey affect and in the severity and duration of the paralysis theyevoke. For example, it has been determined that Botulinum toxin type Ais 500 times more potent, as measured by the rate of paralysis producedin the rat, than is Botulinum toxin type B. Additionally, Botulinumtoxin type B has been determined to be non-toxic in primates at a doseof 480 U/kg which is about 12 times the primate LD₅₀ for Botulinum toxintype A (Moyer et al., “Botulinum Toxin Type B: Experimental and ClinicalExperience,” in Therapy With Botulinum Toxin, Marcel Dekker, IncJankovic et al. (eds.), pgs. 71-85, 1994).

Depression: A mental state of depressed mood characterized by feelingsof sadness, despair and discouragement. Depression includes feelings ofsadness considered to be normal (mild depression), dysthymia, and majordepression. Depression can resemble the grief and mourning that followsbereavement, and there are often feelings of low self esteem, guilt andself reproach, withdrawal from interpersonal contact and somaticsymptoms such as alterations in eating habits and sleep disturbances.

Frown: To furrow the brow to show unhappiness or displeasure. Thisaction uses the orbicularis oculi, the frontalis muscle and/or thecorrugator supercilii muscle. This action can also include the use ofthe procerus muscle.

Pharmaceutically acceptable carriers: The pharmaceutically acceptablecarriers useful in this invention are conventional. Remington'sPharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton,Pa., 15th Edition (1975), describes compositions and formulationssuitable for pharmaceutical delivery of the fusion proteins hereindisclosed.

In general, the nature of the carrier will depend on the particular modeof administration being employed. In addition to biologically-neutralcarriers, pharmaceutical compositions to be administered can containminor amounts of non-toxic auxiliary substances, such as wetting oremulsifying agents, preservatives, and pH buffering agents and the like,for example, sodium acetate or sorbitan monolaurate.

Psychotic: A psychiatric condition in its broadest sense, as defined inthe DSM-WV (Kaplan, ed. (1995) supra) and described below. Differentdisorders which have a psychotic component comprise different aspects ofthis definition of “psychotic.” For example, in schizophreniformdisorder, schizoaffective disorder and brief psychotic disorder, theterm “psychotic” refers to delusions, any prominent hallucinations,disorganized speech, or disorganized or catatonic behavior. In psychoticdisorder due to a general medical condition and in substance-inducedpsychotic disorder, “psychotic” refers to delusions or only thosehallucinations that are not accompanied by insight. Finally, indelusional disorder and shared psychotic disorder, “psychotic” isequivalent to “delusional” (see DSM-IV, supra, page 273).

Objective tests can be used to determine whether an individual ispsychotic and to measure and assess the success of a particulartreatment schedule or regimen. For example, measuring changes incognitive ability aids in the diagnosis and treatment assessment of thepsychotic patient. Any test known in the art can be used, such as theso-called “Wallach Test,” which assesses recognition memory (see below,Wallach, J Gerontol. 35:371-375, 1980). Another example of an objectivetext that can be used to determine whether an individual is psychoticand to measure efficacy of an anti-psychotic treatment is the StroopColor and Word Test (“Stroop Test”) (see Golden, C. J., Cat. No. 30150M,in A Manual for Clinical and Experimental Uses, Stoelting, Wood Dale,Ill.). The Stroop Test is an objective neuropsychiatric test that candifferentiate between individuals with psychosis and those without.

Psychosis: A psychiatric symptom, condition or syndrome in its broadestsense, as defined in the DSM-IV (Kaplan, ed. (1995) supra), comprising a“psychotic” component, as broadly defined above. Psychosis is typicallydefined as a mental disorder or condition causing gross distortion ordisorganization of a person's mental capacity, affective response, andcapacity to recognize reality, communicate, and relate to others to thedegree of interfering with his capacity to cope with the ordinarydemands of everyday life.

Psychotic major depression: A condition also referred to as psychoticdepression (Schatzberg, Am. J Psychiatry 149:733-745, 1992), “psychotic(delusional) depression,” “delusional depression,” and “major depressionwith psychotic features” (see the DSM-III-R). This condition is adistinct psychiatric disorder that includes both depressive andpsychotic features. Individuals manifesting both depression andpsychosis, i.e. psychotic depression, are often referred to as“psychotic depressives.”

Scowl: A facial expression showing displeasure. Scowling primarilyutilizes the corrugator supercilii muscle and the procerus muscle.

Subject: Any mammal. In one embodiment, a subject is a human subject.

Therapeutically effective amount: A quantity of treatment, such as drug,for example a neurotoxin such as Botulinum toxin A, sufficient toachieve a desired effect in a subject being treated. For instance, thiscan be the amount of Botulinum toxin A necessary to impair contractionof, or paralyze, a facial muscle. This can also be the amount of atherapy, such as light therapy or psychotherapy, sufficient to relieve asymptom of a disorder, such as depression. This can also be the amountof an antidepressant sufficient to alter the mood of a subject.

Unit equivalents: An amount of Botulinum Toxin (BTX) that is equivalentto standard Units of Botulinum Toxin A (BTX-A). A standard Unit of BTX-Ais defined as the mean LD₅₀ for female Swiss Webster mice weighing 18-20grams (Schantz and Kaultner, J. Assoc. Anal. Chem. 61: 96-99, 1978). Theestimated human LD₅₀ for a 70-kg person is 40 Units/kg or about2500-3000 Units.

BOTOX™ (Botulinum toxin A, Allergan, Inc., Irvine, Calif., U.S.A.) issold in 100 Unit vials. DYSPORT™ (Speywood Pharmaceuticals, Ltd.,Maidenhead, U.K.) is sold in 500 Unit vials. For cosmetic uses, the vialcontents are typically diluted with 1 or 2 ml of sterile salinesolution, which for BOTOX™ provides a 100 or 50 Unit/ml dilution.DYSPORT™ BTX-A is roughly tenfold less toxic than BOTOX™ andapproximately fourfold greater amounts of the DYSPORT™ product willusually be injected to achieve the same result as would be obtainedusing a specific number of Units of BOTOX™.

Unless otherwise explained, all technical and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which this disclosure belongs. The singular terms“a,” “an,” and “the” include plural referents unless the context clearlyindicates otherwise. Similarly, the word “or” is intended to include“and” unless the context clearly indicates otherwise. It is further tobe understood that all base sizes or amino acid sizes, and all molecularweight or molecular mass values, given for nucleic acids or polypeptidesare approximate, and are provided for description. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of this disclosure, suitable methods andmaterials are described below. The term “comprises” means “includes.”All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety. Incase of conflict, the present specification, including explanations ofterms, will control. In addition, the materials, methods, and examplesare illustrative only and not intended to be limiting.

Botulinum Toxin

Botulinum toxin (BTX), produced by the bacterium Clostridium botulinumreversibly paralyzes striated muscle when administered in sub-lethaldoses. BTX has been used in the treatment in a number of neuromusculardisorders and conditions involving muscular spasm including, but notlimited to, dystonia, hemifacial spasm, tremor, spasticity (e.g.resulting from multiple sclerosis), anal fissures and variousophthalmologic conditions (for example, see Carruthers et al., J Amer.Acad. Derm. 34:788-797, 1996). A Botulinum toxin type A complex has beenapproved by the U.S. Food and Drug Administration for the treatment ofblepharospasm, strabismus and hemifacial spasm.

BTX is a generic term covering a family of toxins produced by C.botulinum comprising up to eight serologically distinct forms (A, B, C₁,C₂, D, E, F and G). These toxins are among the most powerfulneuroparalytic agents known (c.f. Melling et al., Eye 2:16-23, 1988).Serotypes A, B and F are the most potent. Without being bound by theory,the mode of action is believed to be an inhibition of the release ofacetylcholine by the presynaptic nerve.

Botulinum toxin type A can be obtained by establishing and growingcultures of Clostridium botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known procedures.Alternatively, the Botulinum toxin serotypes are initially synthesizedas inactive single chain proteins which must be cleaved or nicked byproteases to become neuroactive. High quality crystalline Botulinumtoxin type A can be produced from the Hall A strain of Clostridiumbotulinum. The Schantz process can be used to obtain crystallineBotulinum toxin type A (see Schantz et al., Microbiol Rev. 56; 80-99,1992). Generally, the Botulinum toxin type A complex can be isolated andpurified from an anaerobic fermentation by cultivating Clostridiumbotulinum type A in a suitable medium. This process can be used, uponseparation out of the non-toxin proteins, to obtain pure Botulinumtoxins, such as for example: purified Botulinum toxin type A with anapproximately 150 kD molecular weight, purified Botulinum toxin type Bwith an approximately 156 kD molecular weight and purified Botulinumtoxin type F with an approximately 155 kD molecular weight.

Botulinum toxins and/or Botulinum toxin complexes can be obtained fromList Biological Laboratories, Inc., Campbell, Calif.; the Centre forApplied Microbiology and Research, Porton Down, U.K.; Wako, Osaka,Japan; Metabiologics, Madison, Wis.) as well as from Sigma Chemicals, StLouis, Mo.

The initial cosmetic use of BTX was for treatment of forehead frownlines as reported in Carruthers and Carruthers, J. Dermatol. Surg.Oncol. 18:17-21, 1992. The clinical effects of peripheral intramuscularBotulinum toxin type A are usually seen within one week of injection.The typical duration of symptomatic relief from a single intramuscularinjection of Botulinum toxin type A averages about three months. BTX-Aserotype is available commercially for pharmaceutical use under thetrademarks BOTOX™ (Allergan, Inc., Irvine, Calif., U.S.A.) and DYSPORT™(Speywood Pharmaceuticals, Ltd., Maidenhead, U. K.). BOTOX™ consists ofa purified Botulinum toxin type A complex, albumin and sodium chloridepackaged in sterile, vacuum-dried form. Specifically, each vial ofBOTOX™ contains about 100 Units (U) of Clostridium botulinum toxin typeA purified neurotoxin complex, 0.5 milligrams of human serum albumin and0.9 milligrams of sodium chloride in a sterile, vacuum-dried formwithout a preservative.

The Botulinum toxin type A is made from a culture of the Hall strain ofClostridium botulinum grown in a medium containing N-Z amine and yeastextract. The Botulinum toxin type A complex is purified from the culturesolution by a series of acid precipitations to a crystalline complexconsisting of the active high molecular weight toxin protein and anassociated hemagglutinin protein. The crystalline complex isre-dissolved in a solution containing saline and albumin and sterilefiltered (0.2 microns) prior to vacuum-drying. The vacuum-dried productis stored in a freezer at or below −5° C.

BOTOX™ is sold in 100 Unit vials. DYSPORT™ is sold in 500 Unit vials.BTX-A is roughly tenfold less toxic than BOTOX™ and approximatelyfourfold greater amounts of the DYSPORT™ product will usually beinjected to achieve the same result as would be obtained using aspecific number of Units of BOTOX™.

For cosmetic uses, the vial contents are typically diluted with 1 or 2ml of sterile saline solution, which for BOTOX™ provides a 100 or 50Unit/ml dilution. (DYSPORT™ can also be utilized.) For example, BOTOX™can be reconstituted with sterile, non-preserved saline prior tointramuscular injection. To reconstitute vacuum-dried BOTOX™, sterilenormal saline without a preservative (0.9% Sodium Chloride Injection) isused by drawing up the proper amount of diluent in the appropriate sizesyringe. Since BOTOX™ may be denatured by bubbling or similar violentagitation, the diluent is gently injected into the vial. For sterilityreasons BOTOX™ is preferably administered within four hours after thevial is removed from the freezer and reconstituted. During these fourhours, reconstituted BOTOX™ can be stored in a refrigerator at about 2°C. to about 8° C. Reconstituted, refrigerated BOTOX′ has been reportedto retain its potency for at least about two weeks (see Neurology,48:249-53:1997).

Methods for Treatment of Depression

A method is provided herein for treating depression. The method includesadministering a therapeutically effective amount of an agent (such as aneurotoxin) to a facial muscle involved in frowning, scowling, or a sadappearance. The agent causes partial or complete paralysis of the facialmuscle, thereby affecting the ability of the subject to frown and/orscowl, or appear sad, and thereby treat depression. For example, atherapeutically effective amount of BTX can be injected into one or moreof the orbicularis oculi, frontalis, procerus, the corrugatorsupercilii, or the depressor anguli oris (trianglaris muscle).

The method involves identifying or selecting persons who are depressed,and administering the treatment to them. Any form of depression can betreated herein, including mild depression, dysthymia and majordepression. The depression can be the result of a mood disorder, and maybe accompanied by an anxiety disorder. Without being bound by theory,decreased movement of muscles that contribute to the depressed facieshelps elevate mood, and thus a lessening of the feeling of depressionensues. Denervation of the frown and scowl muscles results in adecreased ability of the treated subject to frown or scowl, and thuscontributes to a subjective sense of elevated mood. Such improved moodcan be objectively assessed by the DSM-IV criteria, or by standardizedtests known in the art to determine whether a subject is depressed.Depression can be assessed, for example, by the Beck DepressionInventory II (1996, Harcourt). A very straightforward test is to ask thesubject to report whether his or her mood has improved, or to ratefeelings of depression on a numerical scale. Specific questions can alsobe asked about feelings of sadness and hopelessness, as well as changesin physical signs and symptoms associated with depression, such aneurovegetative complaints or psychomotor retardation.

The treatment can be repeated when the partial or complete muscleparalysis induced by the agent begins to abate. Alternatively, one canalso wait for any signs or symptoms of depression to also recur afterthe muscular activity returns.

An exemplary injection technique involves the use of a short, narrowneedle (e.g. ½ inch or 8 mm; 30-gauge) with an insulin- ortuberculin-type syringe. Subjects are typically treated in the seatedposition. The skin area is cleaned with an alcohol swab. A singlesyringe may be used for multiple injections to treat different locationsin a single muscle or different locations on a patient's face.Typically, the plunger of the syringe is depressed as the needle iswithdrawn so that toxin is evenly distributed at the injection site.Pressure or gentle massage may be applied at the injection site toassist in dissipating the toxin. The toxin will typically migrateapproximately 1 cm from the site of injection.

Electromyographic (EMG) guided needles may be used for injection todetermine needle location of a high degree of accuracy, although thistechnique is generally not necessary.

For applications of BTX, total dose per treatment can be varied anddepends upon the condition being treated and the site of application ofBTX. For example, a total dose of 10-50 Units (such as about 20 to about40 Unit equivalents) will typically be applied to the glabellar complexand 60-75 Units for platysmal bands (Carruthers and Carruthers,Dermatol. Surg. 24:1168-1170, 1998). In one specific non-limitingexample, about 30 to about 50 Unit equivalents of BTX is administered tothe frontalis and/or the procerus muscle.

Onset of muscle paralysis following injection usually occurs withinhours of treatment. The duration of paralysis will vary from patient topatient. Typically, duration will be from two to eight months, forexample about three to about six months, or for example about threemonths, before subsequent treatment is required to alleviate thecondition, although Botulinum toxin type A can have an efficacy for upto 12 months (Naumann et al., European J. Neurology 6(Supp 4):S111-S115,1999).

Thus, in one specific, non-limiting example, to treat depression, amuscle involved in frowning or scowling is treated repeatedly. Forexample, about 30 to about 50 Unit equivalents of BTX is administered tothe frontalis and/or the procerus muscle. After a period of about threemonths, and additional about 30 to about 50 Unit equivalents of BTX isadministered to the corrugator supercilii, orbicularis oculi, procerus,and/or frontalis muscle. This treatment can be administered as manytimes as need to alleviate depression of the subject.

FIGS. 2 and 3 show Botulinum toxin dose used to treat the frown and/orscowl in a typical woman (FIG. 2) and man (FIG. 3). The landmarks forthe injection are as follows (see also Carruthers et al., Derm. Surg.24:1189-1194, 1998). The injection of the procerus is below a linejoining the medial end of both eyebrows. The landmark for the nextinjections is a line vertically above the inner canthus and the superiormargin of the orbit. Botulinum toxin is injected just superior to thefirst injection point. Next an injection is made 1 cm above the bone rimin the midpupullary line. The numbers refer to the number of BTX Unitsinjected in the area shown.

In one specific, non-limiting example, for those patients with a sadappearance to their mouth, BTX is injected into the depressor angulioris muscle. In such treatment, the orbicularis oris muscle surroundingthe mouth is normally avoided in view of its sensitivity to BTX.

The depressor anguli oris can be found by instructing the patient tovoluntarily and forcibly pull down the corners of the mouth. Thedepressor anguli oris can be then felt by pulling inferiorly at a pointapproximately 1 cm lateral and 8 mm inferior to the commissure.Alternatively, EMG localization may be performed.

Treatment should take into consideration the pre-existing symmetry ofthe mouth and is performed on both sides of the face in order to providea symmetric result. The required dosage to each side of the mouth shouldbe judged and if necessary, altered upon re-treatment.

Injection may be made into any part of the depressor anguli orismusculature. The injection is intramuscular and may be performed usingthe injection techniques used for other BTX treatments as describedabove. On a typical patient's face, an exemplary point of injection intothe depressor anguli oris is approximately 1 cm laterally and 8 mminferior from the corner of the mouth. A single injection will usuallysuffice with the dosage for a single depressor anguli oris muscleranging from 3 (±10%) Units to 5 (±10%) Units. However, the dose dependsupon the sex of the subject and size of the individual. Exemplary dosesfor a female are 2 (±10%) Units—3 (±10%) Units for one side of themouth; and, for a male, 3 (±10%) Units to 5 (±10%) Units for one side ofthe mouth. Treatment generally does not affect normal speech, whistlingor mastication particularly in cases where the orbicularis oris is nottreated.

In one embodiment, a therapeutically effective amount of BTX isadministered in combination with at least one additional modality oftreatment for depression. The modality can be the administration of atherapeutically effective amount of an antidepressant. The modality oftreatment can also be physical, such as electroconvulsive therapy, lighttherapy, or electromagnetic radiation. The modality can also bepsychotherapy or exercise. A single modality of treatment can becombined with the BTX treatment, or a combination of additionalmodalities can be used with the BTX treatment. In particular examples,the additional modality is the administration of a therapeuticallyeffective amount of an antidepressant medication, such as a tricyclicantidepressant or a selective serotonin reuptake inhibitor (SSRI), orother classes of drugs (such as an MAOI or a tricyclic antidepressant).The BTX can be administered simultaneously or sequentially with theadditional modality of treatment. Thus, in one example, a subject takinga therapeutically effective amount of an antidepressant medication (suchas an SSRI), or undergoing a therapeutic protocol, can be treated withBTX during the course of the additional treatment. Alternatively, BTXcan be administered after the treatment has been terminated, or prior tothe initiation of therapy, such as the administration of theantidepressant medication, psychotherapy, or a physical treatmentprotocol. In one specific example, BTX is administered to a subject whois also taking a therapeutically effective amount of an SSRI.

This disclosure is illustrated by the following non-limiting Examples.

EXAMPLES Example 1 Patient 1

A 59-year-old Caucasian female with a history of depression for 3 yearswas treated. Medications included PAXIL® (20 mg), as prescribed by herpsychiatrist. She appeared somewhat depressed at the time of the firstoffice visit. Her glabellar frown lines and forehead lines were treatedwith 40 i.u. of BOTOX™ (FIG. 4).

Three months later the patient returned for re-treatment. The patientstated that she no longer felt depressed and she attributed herimprovement in her mood to the BOTOX™. Her glabellar frown lines andforehead lines were treated with 40 i.u. of BOTOX™. In a telephonefollow-up interview two months later, the patient reported feeling welland that she was no longer depressed.

This example illustrates that BOTOX™ injection can be used incombination with other treatment modalities (such as antidepressantmedications, for example tricyclic antidepressants, serotonin specificreuptake inhibitors (SSRIs), norepinephrine reuptake inhibitors,monoamine oxidase inhibitors (MAOIs), and others). It is alsoanticipated that the injection could be used in combination with othertherapies, such as psychotherapy.

Example 2 Patient 2

A 33-year-old Caucasian female with a history of intermittentanxiety/depression for ten years was treated. Her medications includedan SSRI (ZOLOFT®, 200 mg per day) for the last four years. Prior totreatment she reported feeling depressed and anxious.

Her frown/glabellar lines were injected with 30 Unit equivalents ofBOTOX™ (FIG. 5). Three months later she returned to the office for afollow-up appointment. She stated that she felt happier during the lastcouple of months than she had in years. Her frown/glabellar lines werere-treated at that time with 30 Unit equivalents of BOTOX™.

Example 3 Patient 3

A 50-year-old, recently divorced, Caucasian female was treated. She hada history of depression for two years. Her medications included PAXIL®20 mg orally per day and WELLBUTRIN® 225 mg orally per day. She reportedfeeling depressed. Her frown/glabellar lines were injected with 30 Unitequivalents of BOTOX™ (FIG. 6). Four months later she reported amuch-improved mood, and stated that she did not feel depressed. Herfrown/glabellar lines were re-treated with 30 Unit equivalents ofBOTOX™.

Example 4 Patient 4

A 63 year-old Caucasian female had a history of a moderately severechronic depression for 20 years. During the past twenty years she hadundergone treatment with various combinations of SSRI's and tricyclicantidepressants. Her medications at the time of her first office visitincluded an SSRI, ZOLOFT®, 200 mg orally per day and WELLBUTRIN®225 mgorally per day, as prescribed by her psychiatrist. She was evaluated bythe Beck Depression Inventory (1996, Harcourt). Her pretreatment scorewas 27, indicative of an ongoing major clinical depression. Physicalexam revealed very prominent frown lines.

She was treated with 30 Unit equivalents of BOTOX™ injected into herglabellar frown lines. At follow-up 6 weeks later she stated that shehad not felt this well in years. Objective evaluation revealed afollow-up score of 5 on the Beck's scale, indicating that she was nolonger clinically depressed.

It will be apparent that the precise details of the methods orcompositions described may be varied or modified without departing fromthe spirit of the described invention. I claim all such modificationsand variations that fall within the scope and spirit of the claimsbelow.

I claim:
 1. A method for treating an affective disorder in a subject,comprising: administering a therapeutically effective amount of acomposition comprising a botulinum toxin to one or more facial muscleinvolved in frowning, scowling or a sad appearance; wherein thetherapeutically effective amount is an amount sufficient to causeparalysis of the one or more facial muscle; thereby treating theaffective disorder in the subject.
 2. The method of claim 1, wherein theone or more facial muscle involved in frowning, scowling or a sadappearance is selected from the group consisting of frontalis,orbicularis oculi, procerus, corrugator supercilii, and depressor angulioris muscle.
 3. The method of claim 1, wherein the one or more facialmuscle is a frontalis muscle, an orbicularis oculi muscle, or a procerusmuscle.
 4. The method of claim 1, wherein the one or more facial muscleis a corrugator supercilii muscle, or a procerus muscle.
 5. The methodof claim 1, wherein the botulinum toxin in the composition is selectedfrom the group consisting of the botulinum toxins types A, B, C₁, D, E,F and G.
 6. The method of claim 5, wherein the botulinum toxin in thecomposition is botulinum toxin A.
 7. The method of claim 1, wherein thetherapeutically effective amount is about 5-60 Unit equivalents of abotulinum toxin type A.
 8. The method of claim 7, further comprisingadministering a second composition comprising an additionaltherapeutically effective amount of the botulinum toxin type A to theone or more facial muscle after about two to six months.
 9. The methodof claim 1, further comprising administering to the subject atherapeutically effective amount of an additional modality of treatmentfor depression.
 10. The method of claim 9, wherein the additionalmodality of treatment comprises administration of an antidepressant,psychotherapy, or a physical treatment for depression.
 11. The method ofclaim 9, wherein the additional modality of treatment comprises aselective serotonin reuptake inhibitor.